Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities such as reproduction, development and wound repair. Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases”) are caused or exacerbated by unregulated angiogenesis. For example, ocular neovascularization has been implicated as the most common cause of blindness. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (J. Folkman, Cancer Res., 46:467-473 (1986), J. Folkman, J. Natl. Cancer Inst., 82:4-6 (1989)). It has been shown, for example, that tumors which enlarge to greater than 2 mm obtain their own blood supply by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as the liver, lungs, and bones (N. Weidner, et. al., N. Engl. J. Med., 324:1-8 (1991)).
Vascular endothelial growth factor (VEGF) has been identified as an extremely powerful angiogenic factor and is required for the growth and metastasis of many human tumours. Much research has focused on attempting to inhibit the VEGF pathway so as to limit or prevent angiogenesis or metastasis. Fairbrother et al: ‘Novel peptides selected to bind vascular endothelial growth factor target the receptor-binding site’ (Biochemistry, 1998, 37, 17754-17764) discloses peptides with varying abilities to bind to VEGF. Various peptides have been identified that bind to the angiogenesis related factor angiopoietin-2 (“Ang-2”) (Oliner, J. et al., Cancer Cell, 204(6), 507-516 (2004)). The Ang-2 binding peptides have been shown to possess anti-angiogenic activity.
It would be desirable to provide compounds that show improved characteristics over known compounds, such as for example, improved binding to VEGF. It would be further desirable to provide compounds showing binding to both VEGF and Ang2.
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